Transplantation of vital organs such as the heart, liver, kidney, pancreas, and lung has become increasingly successful and sophisticated in recent years. Because mammalian organs progressively lose their ability to function during storage, even at ice temperatures, transplant operations need to be performed expeditiously after organ procurement so as to minimize the period of time that the organ is without supportive blood flow. This is particularly true for the heart in which the permissible storage time with present methods of preservation is limited to a maximum of about 4 to 6 hours.
In clinical practice, the two situations in which cardiac preservation is required are heart transplantation and cardioplegia for open heart surgery. In heart transplantation, the donor heart is exposed through a midline sternotomy. After opening the pericardium, the superior and inferior vena cavae and the ascending aorta are isolated. The venous inflow is then occluded, the aorta is cross clamped, and approximately 1 liter of cold cardioplegic solution is flushed into the aortic root under pressure through a needle. As a result, the heart is immediately arrested, and cooling is supplemented by surrounding it with iced saline. The cold arrested heart is then surgically excised, immersed in cold cardioplegic solution, surround by ice and rushed to the recipient center.
The recipient's chest is opened through a midline sternotomy, and after placing the patient on cardiopulmonary bypass, the diseased heart is excised. The preserved donor heart is then removed from the preservation apparatus, trimmed appropriately and sewn to the stumps of the great vessels and the two atria in the chest. After completion of the vascular anastomoses, blood is allowed to return to the heart. It then will either resume beating spontaneously or will require chemical and electical treatment to restore normal rhythm. When the heart is ready to take over the circulation, the cardiopulmonary bypass is discontinued and the recipient's chest closed.
Most non transplant surgical procedures on the heart, such as coronary artery bypass grafting, require that the heart's action be arrested for a period ranging from 1 to 4 hours. During this time, the heart is kept cool by external cooling as well as by periodic reflushing a cardioplegic solution through the coronary arteries. The composition of the latter solution is designed to rapidly arrest the heart and to keep it in good condition during the period of standstill so that it will resume normal function when the procedure is finished.
In the cardioplegic procedure, the heart is exposed in the chest, and as a minimum the aortic root is isolated. A vascular clamp is applied across the aorta and approximately 1 liter of cold cardioplegic solution is flushed into the aortic root through a needle. Venting is provided through the left ventricle, pulmonary artery or the right atrium and the effluent which may contain high levels of potassium is sucked out of the chest. This, together with external cooling, produces rapid cessation of contractions. During the period of arrest, the patient's circulation is maintained artificially using cardiopulmonary bypass.
After completion of the surgical procedure, blood flow is restored to the coronary circulation and beating either returns spontaneously or after chemical and electric treatment. The ease with which stable function is restored depends to a large extent on the effectiveness of preservation by the cardioplegic solution. Once the heart is beating satisfactorily, cardiopulmonary bypass is discontinued and the chest closed.
It is generally understood that "living" organs, including the heart, continue the process of metabolism after removal from the donor so that cell constituents are continuously metabolized to waste products. The accumulation of these metabolic waste products, depletion of cell nutrients and consequent derangement of cell composition lead to progressive loss of function and ultimately to cell death if the storage technique is inadequate. That is, the organ will lose its ability to function adequately after transplantation into the recipient. Several procedures have been successfully explored to enable organs to be preserved ex vivo for useful time periods. In one method the organ to be transplanted is rapidly cooled by flushing cold solutions through the organ's vascular system and maintaining the organ at temperatures near 0.degree. C. for the purpose of greatly slowing the metabolic rate. In the case of the mammalian heart, the flush solution composition is designed to cause the heart to rapidly stop beating as well as to preserve it.
Another method for organ storage utilizes continuous perfusion at temperatures in the range of 7.degree.-10.degree. C. with an oxygenated solution designed to support oxidative metabolism and to remove waste products. A suitable perfusate is delivered through the circulatory system of the isolated organ--usually from the arterial side--and as the perfusate is conveyed through the vascular system waste products are carried away from the organ. Kidneys and livers can commonly be preserved in this manner for several days. However, only limited success has been achieved in preserving the heart, and therefore this method is not used in clinical heart transplantation. The heart must function well enough to sustain a good circulation in the recipient immediately after the transplant operation, whereas some impairment of function can be tolerated in transplanted livers and kidneys. Since hearts can only be preserved for 4-6 hours using cardioplegic solutions, heart transplantation tends to be ruled out in certain situations in which the proposed donor and recipient are far distant from one another.
The viability of a preserved organ depends on a number of factors, among which may be listed (1) cell swelling which occurs at low temperatures as water is transferred across cell membranes in a stored organ, (2) the degree of intracellular acidosis which occurs during non perfused ice storage as a consequence of continued cell metabolism, (3) derangement of internal cell composition which results from impaired metabolism, particularly with respect to cations such as calcium, potassium, magnesium and sodium, and (4) injury caused by oxygen-derived free radicals during oxygenated perfusion or after restoration of the circulation.
Perfusate solutions containing hydroxyethyl starch ("HES") have been reported by Belzer and Southard in Transplantation, 45:673 676, April, 1988, for use in preserving the kidney, liver and pancreas. See also PCT Publication No. WO 87/01940 (published Apr. 9, 1987). The compositions differ depending on whether they are to be used for continuous perfusion or a single flush ice storage of the organ. In both cases, however, a central feature of the solution is the content of the colloid HES.